ABSTRACT Administrative Supplement Request (2019) to R01 MH 108509 ? Functional Neuroanatomy Correlates of Worry in Older Adults Severe worry, defined as intense, uncontrollable worry associated with reduced quality of life, is surprisingly prevalent in the community, with 20% of older adults reporting severe worry. The notable morbidity associated with severe worry, especially related to cardiovascular events and cognitive disorders, has only recently been recognized. This proposed administrative supplement will explore the effect of severe worry on accelerated aging through two different but equally relevant pathways: hippocampal atrophy and vascular burden. In our previous supplement [3R01 MH108509-03S1], we proposed to examine the effect of severe worry on amyloid burden through chronic markers of stress. Taken together, the current proposal and the previous supplement would allow us to explore a comprehensive model of the three putative pathways through which severe worry may increase the risk of AD. We propose to add to the extensive clinical, neuroimaging and neuropsychological measures used in R01 MH 108509, measures of cerebral small vessel disease [cerebral arteriolar tortuosity measured by Time-of-Flight TOF imaging) and arteriolar microbleeds measured by Susceptibility-Weighted Imaging SWI)], measures of peripheral vascular disease [carotid artery intima medial thickness (ITM) and pulse wave velocity (PWV)] , and measures of hippocampal atrophy and glutamate excitotoxicity (high-field hippocampal subfield analysis and hippocampal single-voxel MR spectroscopy). As multiple studies highlight that women, when transitioning through menopause, experience de-novo or worsening generalized anxiety and severe worry, we plan to additionally explore both the effect of gender on the association between severe worry and cardiovascular risk as well as the effect of perimenopause on the above association. These additional measures will be collected for a 12-month period in participants enrolled in the parent R01. We will include a sample of 40 participants, including high- and low- worry participants, male and females age 50-60. Together with the neurocognitive data collected in the parent R01 and the beta amyloid PET scans collected through the 2018 supplement, the data obtained through this supplement will be used for future studies designed 1) to test the model that severe worry augments the risk of AD through three convergent pathways; 2) to apply the proposed mechanism to a longitudinal interventional study targeting severe worry while monitoring markers of excitotoxicity and vascular burden, and 3) to develop a fully powered longitudinal study focused on the interplay of severe worry, perimenopausal hormonal changes and risk of dementia.